Researchers in the United Kingdom yesterday posted the results of a first-of-its-kind study in which healthy young volunteers were purposely infected with an early strain of the pandemic coronavirus. As hoped, none of the participants got seriously ill, and scientists were able to closely track their symptoms and gain unique insight into how both SARS-CoV-2 levels and symptoms vary from start to finish during an infection.
The success of this initial “human challenge” study provides a strategy for testing COVID-19 treatments, vaccines, and viral variants going forward, the researchers say. The study may also help scientists understand why the pandemic coronavirus can breach the immune defenses of some people but not others.
In the study, 34 healthy volunteers ages 18 to 29 were given nose drops with a small amount of the virus. Eighteen, or 53%, became infected, according to polymerase chain reaction (PCR) tests. Most volunteers developed mild to moderate symptoms but none needed hospitalization or treatment, showing the study could be done safely, according to the investigators who ran it. The study also found that after the first 1 to 2 days of infection, rapid antigen tests reliably indicated the presence of virus.
The results, posted on a preprint server, have not yet been peer reviewed but are under review at a Nature journal.
“It’s a very important piece of work,” says David Dowdy, an infectious disease epidemiologist at the Johns Hopkins School of Public Health. “None of the other research that’s out there is able to track … both the symptoms and the immunology from a known time of infection.”
“It’s really a first glimpse at what happens from the very beginning of the infection,” adds Akiko Iwasaki, an immunologist at Yale University. “Fortunately all these people who were infected had mild disease. That’s a good thing. Because these challenge experiments always have the risk for developing severe disease.”
Scientists have long conducted human challenge studies for various pathogens, including the influenza virus, but ethics questions mount if there are no established treatments for an infection that turns serious.
Human challenge studies for SARS-CoV-2 garnered interest early in the pandemic, but as successful COVID-19 vaccines were developed, various groups abandoned their plans, including a team at the U.S. National Institutes of Health (NIH) that had drawn up a detailed experimental protocol. A large U.K. consortium funded with more than £33 million from the U.K. government pressed on.
They launched their trial in early 2021 with a viral strain that had circulated in the United Kingdom in July 2020, early in the pandemic. None of the 26 male and eight female volunteers had been vaccinated or had had a natural SARS-CoV-2 infection. Volunteers were infected with a low dose—about equivalent to the amount of virus in one drop of nasal fluid when they were at their most infectious—in a high-containment quarantine unit at the Royal Free Hospital in London. Researchers monitored their symptoms and tested them intensively with rapid antigen, PCR, antibody, and viral load tests.
Whether because of the low dose, the volunteers’ vigorous immune systems, or both, the virus failed entirely to establish an infection in 16 people who got the nose drops. Because volunteers were all given the same virus in the same way with the same small dose, the findings open a door to studying why and how some people manage to resist infection.
The results also painted a clear time course of viral travel in the body. An average of 2 days after the nose drops were delivered, symptoms began and virus was shed in the throat. Symptoms peaked at about 5 days. That’s also when active virus levels peaked in the nose, where the viral load was much larger than in the throat. Infectious virus stopped being isolated from volunteers’ noses an average of 10 days after infection.
Only two volunteers with confirmed infection were completely asymptomatic. The other 16 developed mild to moderate symptoms such as nasal stuffiness, sore throat, muscle aches, and fever. Slightly later, 12 volunteers developed disruptions in smell, with nine temporarily losing their sense of smell completely. One still had minor smell abnormalities 6 months later.
Notably, the viral loads in the two volunteers who became infected but had no symptoms were not lower than in their sick colleagues. “Even if people had no symptoms at all … they all generated extremely large amounts of virus, which really speaks to the infectivity [of the virus] and explains how the pandemic has spread so rapidly,” says Chris Chiu, an immunologist at Imperial College London (ICL) who was the study’s chief investigator; he spoke at a Science Media Centre press briefing today.
However, some scientists note—and the researchers acknowledge—that the early virus strain used in the study likely acts differently from more recent variants such as Delta and Omicron, which are more transmissible. “Different variants would require different experiments,” Iwasaki says. “The extent of [virus] replication as well as the duration [of symptoms] might differ somewhat. And potentially even location [of viral load] might differ.”
Future human challenge studies with multiple variants might be used to test vaccines designed to be broadly protective against various strains of SARS-CoV-2 or even other coronaviruses, says Matthew Memoli, a physician and virologist at the U.S. National Institute of Allergy and Infectious Diseases who had developed the planned NIH challenge experiment. “The problem is right now when we make these vaccines we are kinda flying blind,” he says.
Memoli also says the U.K. study pulls back a curtain on basic biology. For instance, it found that uninfected volunteers did not develop SARS-CoV-2 antibodies in their blood. That’s in contrast to flu challenge studies—which Memoli has run for 10 years—in which exposed but uninfected people do develop antibodies. Memoli suspects the difference may be because specialized mucosal antibodies shut down SARS-CoV-2 in the noses of the current study’s uninfected volunteers.
Some critics have pushed back against human challenge studies, arguing that their risks to volunteers outweigh the benefits to society at large.
But study co-investigator Peter Openshaw, a respiratory physician and immunologist at ICL, rejected that at today’s press briefing: “Is it ethical not to do these studies, if they can be done? … We get unique insights. We need to just acknowledge and thank the altruism of the volunteers who stepped forward.”
He and his colleagues are planning their next move: In the spring, they hope to launch a Wellcome Trust–funded human challenge study using a standardized Delta variant in vaccinated volunteers.